Pyridine carboxamide compounds and their use in treating medical conditions

Abstract

The invention provides pyridine carboxamide compounds, pharmaceutical compositions, and their use in treating medical conditions.

1 . A compound represented by Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl; 
         R 1  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , —OCR, C 1-4  aliphatic, C 1-4  haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring or a 3-8 membered saturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R 2  is hydrogen, halo, —OH, —CN, cyclopropyl, C 1-3  alkyl optionally substituted with a group selected from —OH, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 , C 1-3  haloalkyl, or C 1-3  alkoxy; 
         R 3  is hydrogen, cyclopropyl, or C 1-3  alkyl optionally substituted with a group selected from —OH, OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; 
         R 4  is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4  is substituted with p instances of R 5 ; 
         R 5  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , a C 1-3  alkyl group, a C 1-3  haloalkyl group, a C 1-3  heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R represents independently for each occurrence hydrogen, hydroxyl, halo, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 
         n is 0, 1, 2, or 3; and 
         p is 0, 1, 2, 3 or 4. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of Formula I. 
     
     
         3 . The compound of either of  claim 1 or 2 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl. 
     
     
         4 . The compound of any one of  claims 1-3 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         5 . The compound of any one of  claims 1-3 , wherein Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, or a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or phenyl. 
     
     
         6 . The compound of any one of  claims 1-5 , wherein R 1  is —H, —CH 3 , —CH 2 C(O)NH 2 , —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —NHAc, —OH, —C(O)CH 2 OH, —C(O)CH 3 , —CH 2 C(O)NH 2 , —OCH 3 , CH 2 OCH 3 , —C(O)OCH 3 , —C(O)OH, —NHCH 2 CH 2 OH, —CH 2 CH 2 C(O)OCH 3 , —NHS(O) 2 CH 3 , —C(O)NH 2 , —S(O) 2 CH 3 , Bn, —OC(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —F, —Cl, —Br, (O), —CH 2 NH 2 , —NH 2 , —NHC(O)CH 3 , —C(O)OCH 2 CH 3 , —O-cyclopentyl, —S(O) 2 NHCH 2 CH 2 OH, —CH 2 CH 3 , —N(CH 3 ) 2 , —CH(CH 3 ) 2 , —CF 3 , —CN, —S(O) 2 CH 3 , —CH 2 OH, —OCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 2 CH 2 OH, —O(CH 2 ) 3 N(CH 3 ) 2 , —C(O)NH 2 , cyclohexyl, cyclopropyl, —OCF, —S(O) 2 NH 2 , —CHF 2 , —CH 2 NHC(O)OC(CH 3 ) 3 , —C(CH 3 ) 2 (OH), —CH(OH)CH 3 , or —O(CH 2 ) 2 NR 2 . 
     
     
         7 . The compound of any one of  claims 1-6 , wherein R 2  is hydrogen. 
     
     
         8 . The compound of any one of  claims 1-6 , wherein R 2  is C 1-3  alkyl. 
     
     
         9 . The compound of any one of  claims 1-6 , wherein R 2  is methyl. 
     
     
         10 . The compound of any one of  claims 1-6 , wherein R 2  is cyclopropyl. 
     
     
         11 . The compound of any one of  claims 1-10 , wherein R 3  is hydrogen. 
     
     
         12 . The compound of any one of  claims 1-10 , wherein R 3  is C 1-3  alkyl. 
     
     
         13 . The compound of any one of  claims 1-10 , wherein R 3  is cyclopropyl. 
     
     
         14 . The compound of any one of  claims 1-10 , wherein R 3  is C 1-3  alkyl substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . 
     
     
         15 . The compound of  claim 14 , wherein the substitution on C 1-3  alkyl occurs on the C 1-3  alkyl terminal carbon atom. 
     
     
         16 . The compound of any one of  claims 1-6 , wherein R 2  is methyl and R 3  is hydrogen. 
     
     
         17 . The compound of any one of  claims 1-3 or 6-16 , wherein the compound is of Formula I-A, I-B, or I-C: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is nitrogen or carbon. 
       
     
     
         18 . The compound of  claim 17 , wherein X is nitrogen. 
     
     
         19 . The compound of any one of  claims 1-4 or 6-16 , wherein the compound is of Formula I-D: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 19 , wherein R 1  is —CH 3 , R 2  is —CH 3 , and R 3  is —H. 
     
     
         21 . A compound represented by Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl; 
         R 1  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , —OCR, C 1-4  aliphatic, or C 1-4  haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring or a 3-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R 2  is hydrogen, halo, —OH, —CN, cyclopropyl, C 1-3  alkyl optionally substituted with a group selected from —OH, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 , C 1-3  haloalkyl, or C 1-3  alkoxy; 
         R 3  is hydrogen, cyclopropyl, or C 1-3  alkyl optionally substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; 
         R 4  is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4  is substituted with p instances of R 5 ; 
         R 5  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , a C 1-3  alkyl group, a C 1-3  haloalkyl group, a C 1-3  heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         L 1  is a bond, —OCH 2 —, —O—, —OCH 2 CH 2 —, —NHCH 2 —, —NHCH 2 CH 2 —, or —NH—; 
         Y represents independently for each occurrence —R, oxo, —OR, —NR 2 , —OCH 2 CHF 2 , —OCH 2 CH 2 OH, or —NHCH 2 CH 2 OR; or two Y groups attached to the same carbon atom can together form a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R represents independently for each occurrence —H, —OH, halo, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 
         n is 0, 1, 2, or 3; 
         p is 0, 1, 2, 3 or 4; and 
         q is 0, 1 or 2. 
       
     
     
         22 . The compound of  claim 21 , wherein the compound is a compound of Formula II. 
     
     
         23 . The compound of either of  claim 21 or claim 22 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         24 . The compound of any one of  claims 21-23 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         25 . The compound of any one of  claims 21-23 , wherein Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl. 
     
     
         26 . The compound of any one of  claims 21-25 , wherein R 1  is —H, —CH 3 , —CH 2 C(O)NH 2 , —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —NHAc, —OH, —C(O)CH 2 OH, —C(O)CH 3 , —CH 2 C(O)NH 2 , —OCH 3 , CH 2 OCH 3 , —C(O)OCH 3 , —C(O)OH, —NHCH 2 CH 2 OH, —CH 2 CH 2 C(O)OCH 3 , —NHS(O) 2 CH 3 , —C(O)NH 2 , —S(O) 2 CH 3 , Bn, —OC(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —F, —Cl, —Br, (O), —CH 2 NH 2 , —NH 2 , —NHC(O)CH 3 , —C(O)OCH 2 CH 3 , —O-cyclopentyl, —S(O) 2 NHCH 2 CH 2 OH, —CH 2 CH 3 , —N(CH 3 ) 2 , —CH(CH 3 ) 2 , —CF 3 , —CN, —S(O) 2 CH 3 , —CH 2 OH, —OCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 2 CH 2 OH —O(CH 2 ) 3 N(CH 3 ) 2 , —C(O)NH 2 , cyclohexyl, cyclopropyl, —OCF 3 , —S(O) 2 NH 2 , —CHF 2 , —CH 2 NHC(O)OC(CH 3 ) 3 , —C(CH 3 ) 2 (OH), —CH(OH)CH 3 , or —O(CH 2 ) 2 NR 2 . 
     
     
         27 . The compound of any one of  claims 21-26 , wherein R 2  is hydrogen. 
     
     
         28 . The compound of any one of  claims 21-26 , wherein R 2  is C 1-3  alkyl. 
     
     
         29 . The compound of any one of  claims 21-26 , wherein R 2  is methyl. 
     
     
         30 . The compound of any one of  claims 21-26 , wherein R 2  is cyclopropyl. 
     
     
         31 . The compound of any one of  claims 21-30 , wherein R 3  is hydrogen. 
     
     
         32 . The compound of any one of  claims 21-30 , wherein R 3  is C 1-3  alkyl. 
     
     
         33 . The compound of any one of  claims 21-30 , wherein R 3  is cyclopropyl. 
     
     
         34 . The compound of any one of  claims 21-30 , wherein R 3  is C 1-3  alkyl substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . 
     
     
         35 . The compound of  claim 34 , wherein the substitution on C 1-3  alkyl occurs on the C 1-3  alkyl terminal carbon atom. 
     
     
         36 . The compound of any one of  claims 21-26 , wherein R 2  is methyl and R 3  is hydrogen. 
     
     
         37 . The compound of any one of  claims 21-36 , wherein L 1  is a bond, —O—, or —NH—. 
     
     
         38 . The compound of  claim 37 , wherein L 1  is a bond. 
     
     
         39 . A compound represented by Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl; 
         R 1  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , —OCR, C 1-4  aliphatic, or C 1-4  haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring or a 3-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R 2  is hydrogen, halo, —OH, —CN, cyclopropyl, C 1-3  alkyl optionally substituted with a group selected from —OH, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 , C 1-3  haloalkyl, or C 1-3  alkoxy; 
         R 3  is hydrogen, cyclopropyl, or C 1-3  alkyl optionally substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; 
         R 4  is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4  is substituted with p instances of R 5 ; 
         R 5  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , a C 1-3  alkyl group, a C 1-3  haloalkyl group, a C 1-3  heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         X is —O— or —NH—; 
         R represents independently for each occurrence —H, —OH, halo, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 
         n is 0, 1, 2, or 3; and 
         p is 0, 1, 2, 3 or 4. 
       
     
     
         40 . The compound of  claim 39 , wherein the compound is a compound of Formula III. 
     
     
         41 . The compound of either of  claim 39 or claim 40 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         42 . The compound of any one of  claims 39-41 , wherein Ring A is a 6-14 membered saturated or partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         43 . The compound of any one of  claims 39-41 , wherein Ring A is a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an 8-10 membered bicyclic aromatic carbocyclic ring, or phenyl. 
     
     
         44 . The compound of any one of  claims 39-43 , wherein R 1  is —H, —CH 3 , —CH 2 C(O)NH 2 , —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —NHAc, —OH, —C(O)CH 2 OH, —C(O)CH 3 , —CH 2 C(O)NH 2 , —OCH 3 , CH 2 OCH 3 , —C(O)OCH 3 , —C(O)OH, —NHCH 2 CH 2 OH, —CH 2 CH 2 C(O)OCH 3 , —NHS(O) 2 CH 3 , —C(O)NH 2 , —S(O) 2 CH 3 , Bn, —OC(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —F, —Cl, —Br, (O), —CH 2 NH 2 , —CH 2 NHCH 2 CH 2 OH, —NH 2 , —NHC(O)CH 3 , —C(O)OCH 2 CH 3 , —O-cyclopentyl, —S(O) 2 NHCH 2 CH 2 OH, —CH 2 CH 3 , —N(CH 3 ) 2 , —CH(CH 3 ) 2 , —CF 3 , —CN, —S(O) 2 CH 3 , —CH 2 OH, —OCH 3 , —CH 2 N(CH 3 ) 2 , —O(CH 2 ) 3 N(CH 3 ) 2 , —C(O)NH 2 , cyclohexyl, cyclopropyl, —OCF 3 , —S(O) 2 NH 2 , —CHF 2 , —CH 2 NHC(O)OC(CH 3 ) 3 , —C(CH 3 ) 2 (OH), —CH(OH)CH 3 , or —O(CH 2 ) 2 NR 2 . 
     
     
         45 . The compound of any one of  claims 39-44 , wherein R 2  is hydrogen. 
     
     
         46 . The compound of any one of  claims 39-44 , wherein R 2  is C 1-3  alkyl. 
     
     
         47 . The compound of any one of  claims 39-44 , wherein R 2  is methyl. 
     
     
         48 . The compound of any one of  claims 39-44 , wherein R 2  is cyclopropyl. 
     
     
         49 . The compound of any one of  claims 39-48 , wherein R 3  is hydrogen. 
     
     
         50 . The compound of any one of  claims 39-48 , wherein R 3  is C 1-3  alkyl. 
     
     
         51 . The compound of any one of  claims 39-48 , wherein R 3  is cyclopropyl. 
     
     
         52 . The compound of any one of  claims 39-48 , wherein R 3  is C 1-3  alkyl substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . 
     
     
         53 . The compound of  claim 52 , wherein the substitution on C 1-3  alkyl occurs on the C 1-3  alkyl terminal carbon atom. 
     
     
         54 . The compound of any one of  claims 39-44 , wherein R 2  is methyl and R 3  is hydrogen. 
     
     
         55 . The compound of any one of  claims 39-54 , wherein X is —O—. 
     
     
         56 . The compound of any one of  claims 39-54 , wherein X is —NH—. 
     
     
         57 . A compound represented by Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         R 1  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —CH 2 NHCH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , —OCR, C 1-4  aliphatic, or C 1-4  haloaliphatic, or a cyclic group selected from a 3-8 membered saturated monocyclic carbocyclic ring or a 3-8 membered saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R 2  is hydrogen, halo, —OH, —CN, cyclopropyl, C 1-3  alkyl optionally substituted with a group selected from —OH, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 , C 1-3  haloalkyl, or C 1-3  alkoxy; 
         R 3  is hydrogen, cyclopropyl, C 1-3  alkyl optionally substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; 
         R 4  is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 4  is substituted with p instances of R 5 ; 
         R 5  represents independently for each occurrence halo, oxo, —CN, —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)CR 3 , —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —O(CR 2 ) 3 NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —NR(CR 2 ) 2 OR, —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, —CR 3 , —CH 2 NR 2 , —CH 2 NHCH 2 CH 2 OR, —CH 2 CH 2 C(O)OR, —CH 2 C(O)NR 2 , —CH 2 CH 2 R, —CH 2 CH 2 OR, —NHCH 2 CH 2 OR, —NHC(O)R, —CH 2 OR, —CH 2 C(O)NH 2 , —CH 2 NHC(O)OCR 3 , a C 1-3  alkyl group, a C 1-3  haloalkyl group, a C 1-3  heteroalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         R represents independently for each occurrence —H, —OH, halo, or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 
         n is 0, 1, or 2; and 
         p is 0, 1, 2, 3 or 4. 
       
     
     
         58 . The compound of  claim 57 , wherein the compound is a compound of Formula IV. 
     
     
         59 . The compound of either of  claim 57 or claim 58 , wherein R 1  is —H, —CH 3 , —CH 2 C(O)NH 2 , —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —NHAc, —OH, —C(O)CH 2 OH, —C(O)CH 3 , —CH 2 C(O)NH 2 , —OCH 3 , CH 2 OCH 3 , —C(O)OCH 3 , —C(O)OH, —NHCH 2 CH 2 OH, —CH 2 CH 2 C(O)OCH 3 , —NHS(O) 2 CH 3 , —C(O)NH 2 , —S(O) 2 CH 3 , Bn, —OC(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —F, —Cl, —Br, (O), —CH 2 NH 2 , —NH 2 , —NHC(O)CH 3 , —C(O)OCH 2 CH 3 , —O— cyclopentyl, —S(O) 2 NHCH 2 CH 2 OH, —CH 2 CH 3 , —N(CH 3 ) 2 , —CH 2 NHCH 2 CH 2 OH, —CH(CH 3 ) 2 , —CF 3 , —CN, —S(O) 2 CH 3 , —CH 2 OH, —OCH 3 , —CH 2 N(CH 3 ) 2 , —O(CH 2 ) 3 N(CH 3 ) 2 , —C(O)NH 2 , cyclohexyl, cyclopropyl, —OCF 3 , —S(O) 2 NH 2 , —CHF 2 , —CH 2 NHC(O)OC(CH 3 ) 3 , —C(CH 3 ) 2 (OH), —CH(OH)CH 3 , or —O(CH 2 ) 2 NR 2 . 
     
     
         60 . The compound of any one of  claims 57-59 , wherein R 2  is hydrogen. 
     
     
         61 . The compound of any one of  claims 57-59 , wherein R 2  is C 1-3  alkyl. 
     
     
         62 . The compound of any one of  claims 57-59 , wherein R 2  is methyl. 
     
     
         63 . The compound of any one of  claims 57-59 , wherein R 2  is cyclopropyl. 
     
     
         64 . The compound of any one of  claims 57-63 , wherein R 3  is hydrogen. 
     
     
         65 . The compound of any one of  claims 57-63 , wherein R 3  is C 1-3  alkyl. 
     
     
         66 . The compound of any one of  claims 57-63 , wherein R 3  is cyclopropyl. 
     
     
         67 . The compound of any one of  claims 57-63 , wherein R 3  is C 1-3  alkyl substituted with a group selected from —OH, —OMe, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . 
     
     
         68 . The compound of  claim 67 , wherein the substitution on C 1-3  alkyl occurs on the C 1-3  alkyl terminal carbon atom. 
     
     
         69 . The compound of any of one of  claims 57-59 , wherein R 2  is methyl and R 3  is hydrogen. 
     
     
         70 . A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof. 
     
     
         71 . A pharmaceutical composition comprising a compound of any one of  claims 1-70  and a pharmaceutically acceptable carrier. 
     
     
         72 . A method of treating a disorder associated with ABC transporter dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1-70 . 
     
     
         73 . The method of  claim 72 , wherein the disorder associated with ABC transporter dysfunction is characterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4, ABCG5, ABCG8, ABCG1, and ABCG4. 
     
     
         74 . A method of treating a disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1-70 , wherein the disorder is selected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy, Biliary atresia, Alagille syndrome, primary biliary cholangitis, primary sclerosing cholangitis, NAFLD/NASH, Alzheimer's disease, Huntington's disease, Multiple sclerosis, Parkinson's disease, Hirschsprung disease, Zellweger syndrome, Type 2 diabetes, Obesity, Type 1 diabetes, Atherosclerosis, Dyslipidemia, Generalized arterial calcification of infancy, Calciphylaxis, Autosomal recessive cone-rod dystrophy, Gout, PFIC1, Myo5B deficiency cholestasis, PFIC4, and Low phospholipid associated cholelithiasis. 
     
     
         75 . The method of  claim 74 , wherein the disorder is Cystic fibrosis. 
     
     
         76 . The method of any one of  claims 72-75 , wherein the subject is a human.